{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:47:04Z","timestamp":1782398824216,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,23]]},"group-title":"Immunology","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Transforming growth factor-\u03b2 (TGF-\u03b2) regulates CD4 T cell quiescence, activation, and regulatory T cell differentiation, but its role in T cell iron metabolism is poorly defined. Here, we investigated whether TGF-\u03b2 regulates iron homeostasis and how iron overload alters TGF-\u03b2 responsiveness. During T cell activation, TGF-\u03b2 enhanced survival but markedly reduced proliferation. These effects were accompanied by decreased CD71 expression and cytosolic iron availability, as well as increased mitochondrial iron accumulation. Genetic deletion of TGF\u03b2R1 reversed these changes, demonstrating that TGF-\u03b2 regulates CD4 T cell iron homeostasis through TGF\u03b2R1-dependent signaling.<\/jats:p>\n                <jats:p>\n                  Iron-overloaded CD4 T cells lacking the heme exporter FLVCR1 exhibit hypersensitivity to TGF-\u03b2, increased TGF-\u03b2 secretion, and sustained TGF\u03b2R1 expression upon activation. Pharmacologic inhibition of TGF\u03b2R1restored proliferation, CD71 expression, and iron levels in FLVCR1-deficient cells. Although TGF-\u03b2 selectively induced total and mitochondrial ROS levels in FLVCR1-deficient cells, antioxidant treatment or Nox2 inhibition did not rescue this phenotype, suggesting that ROS is associated with, but not sufficient to explain, TGF-\u03b2 hypersensitivity. Acute FeSO\n                  <jats:sub>4<\/jats:sub>\n                  -induced iron overload partially recapitulated the phenotype of FLVCR1-deficient cells, although TGF\u03b2R1 expression and TGF-\u03b2 production differed. Finally, regulatory T cells generated\n                  <jats:italic>in vitro<\/jats:italic>\n                  in the presence of TGF-\u03b2 displayed reduced iron acquisition, and excess iron impaired FoxP3 induction. Together, this work identifies TGF-\u03b2 as a context-dependent regulator of CD4 T cell iron homeostasis.\n                <\/jats:p>","DOI":"10.64898\/2026.06.18.733147","type":"posted-content","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T22:10:13Z","timestamp":1782252613000},"source":"Crossref","is-referenced-by-count":0,"title":["Iron Regulates CD4 T Cell Quiescence by Controlling TGF-\u03b2 Production"],"prefix":"10.64898","author":[{"given":"Amber L.","family":"Siglin","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afia","family":"Nkansah","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WanJun","family":"Chen","sequence":"additional","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD 20892-4352, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheong-Hee","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062506552070000_2026.06.18.733147v1.1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.97.2.329"},{"key":"2026062506552070000_2026.06.18.733147v1.2","doi-asserted-by":"crossref","unstructured":"Pinto JP , Arezes J , Dias V , Oliveira S , Vieira I , Costa M , Vos M , Carlsson A , Rikers Y , Rangel M , et al. 2014. 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The Interplay Between TGF-\u03b2 Signaling and Cell Metabolism. 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Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor. 23(5):358\u2013374.","DOI":"10.1089\/ars.2014.6202"},{"key":"2026062506552070000_2026.06.18.733147v1.25","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2200051"},{"key":"2026062506552070000_2026.06.18.733147v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.07.011"},{"key":"2026062506552070000_2026.06.18.733147v1.27","first-page":"79","article-title":"Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus","volume":"8","year":"2023","journal-title":"Science Immunology"},{"issue":"1","key":"2026062506552070000_2026.06.18.733147v1.28","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3390\/biom13010073","article-title":"Serum Levels of Transforming Growth Factor Beta 1 in Systemic Lupus Erythematosus Patients","volume":"13","year":"2022","journal-title":"Biomolecules"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.18.733147","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:55:58Z","timestamp":1782395758000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.18.733147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":28,"URL":"https:\/\/doi.org\/10.64898\/2026.06.18.733147","relation":{},"subject":[],"published":{"date-parts":[[2026,6,23]]},"subtype":"preprint"}}